The infiltration of lymphocytes into cancer and lesion tissues is a phenomenon which has been clinically known for a long time (Non-Patent Documents 1, 2, 3, 4, and 5). Moreover, numerous experimental and clinical data indicate that infiltrated lymphocytes attack cancer and lesion tissues (Non-Patent Documents 6, 7, and 8).
The main players of cellular immunity in cancer are cytotoxic T cells (CTL) and NK cells (Non-Patent Documents 9, 10, 11, and 12), while the main players of humoral immunity are antibodies produced by plasma cells (Non-Patent Documents 13, 14, and 15). Antibodies that recognize cancer antigens have been shown to be present in the serum of cancer patients and novel cancer antigens have been isolated using antibodies from cancer patients (Non-Patent Documents 16 and 17). Moreover, some of the antibodies produced by plasma cells that infiltrate cancer tissues have been demonstrated to bind to cancer cells (Non-Patent Documents 18, 19, and 20). In addition, antibodies such as Herceptin® and Rituxan®, which recognize antigens strongly expressed in cancers, have been developed as therapeutic drugs, demonstrating the utility of antibodies that recognize cancer-specific antigens (Non-Patent Documents 21 and 22).
Although attempts have been made to separate plasma cells that infiltrate cancer tissues and to continuously produce specific antibodies from those cells, these attempts have failed so far. Reasons for the failure include the inability to secure tumor-specific plasma cells (B lymphocytes) in sufficient numbers because of the difficulty of separating them from cancer tissues, and even if separation were successful to some extent, the instability of antibody production with methods that use EBV or hybridomas for immortalizing antibody-producing cells.
On the other hand, recombinant DNA technologies for creating antibodies having antigen-binding activities similar to those from cloned antibody-producing cells, namely methods for cloning antibody genes and preparing recombinant antibody proteins, are being established (Non-Patent Documents 23 and 24). Antibody genes such as Fv, scFv, Fab, IgG, or IgM (Non-Patent Documents 25, 26, and 27) can be produced by cloning genes encoding the variable regions of antibody genes. scFv, which is the smallest recombinant antibody molecule, has a structure in which a heavy chain variable region and a light chain variable region are joined by a linker.
Cloned B cells express a single antibody gene. Thus, it is easy to clone heavy chain and light chain variable regions from these cells. However, since B cells present in peripheral blood and B cells that infiltrate cancer tissues are cell groups (polyclones) producing various antibodies (Non-Patent Documents 28 and 29), it is extremely difficult to clone cancer-specific genes from these.    [Non-Patent Document 1] Hurliamnn et al. (1985) Int J Cancer 35:753.    [Non-Patent Document 2] Whiteside et al. (1986) Cancer Immunol Immunother 23:169.    [Non-Patent Document 3] Wolf et al. (1986) Otolaryngol Head Neck Surg 95:142.    [Non-Patent Document 4] Husby et al (1976) J Clin Invest 57:1471.    [Non-Patent Document 5] Vose et al. (1979) Int J Cancer 24:579.    [Non-Patent Document 6] Rosenberg et al. (1988) New England J Med 319:1676.    [Non-Patent Document 7] Van Pel et al. (1995) Immunol Reviews 145:229.    [Non-Patent Document 8] Kreider et al. (1984) Cancer Metastasis Rev 3:53.    [Non-Patent Document 9] Nobholz and MacDonald (1983) Annu Rev Immunol 1:273.    [Non-Patent Document 10] Gerundolo et al. (1987) Eur J Immunol 17:173.    [Non-Patent Document 11] Hanna et al., Nat. Immun.Cell Growth Regul., 1983-1984; 3(1):22-33.    [Non-Patent Document 12] Brittenden et al. (1996) Cancer 77:1226.    [Non-Patent Document 13] Roitt et al. (1969) Lancet 2:367.    [Non-Patent Document 14] Borsos (1971) Progress in Immunology: p841. New York, Academic Press.    [Non-Patent Document 15] Kodera and Bean (1975) Int J Cancer 16:579.    [Non-Patent Document 16] Yao-Tseng Chen et al. (1997) Proc Natl Acad Sci USA 94:1914.    [Non-Patent Document 17] Ugur Sahin et al. (1997) Cancer 9:709.    [Non-Patent Document 18] Williams et al. (1996) Jour Immunol 156:1908.    [Non-Patent Document 19] Imahayashi et al. (2000) Cancer Invest 18:530.    [Non-Patent Document 20] Yasuda et al. (2002) Cancer Res 62:1751.    [Non-Patent Document 21] Green et al. (2000) Cancer Treat Rev 26:269.    [Non-Patent Document 22] Maloney et al. (1997) Blood 90:2188.    [Non-Patent Document 23] Marks et al. (1991) J Mol Biol 222:581.    [Non-Patent Document 24] Larrick et al. (1992) Immunol reviews 130:69.    [Non-Patent Document 25] Skerra et al. (1988) Science 240:1038-1041.    [Non-Patent Document 26] Bird et al. (1988) Science 242:423-426.    [Non-Patent Document 27] Better et al. (1988) Science 240:1041-1043.    [Non-Patent Document 28] Kotlan et al. (1999) Immunol Lett 65:143.    [Non-Patent Document 29] Hansen et al. (2001) Pro Natl Acad Sci USA 98:12659.    [Non-Patent Document 30] Blood, 100: 3175-3182, 2002.